Pyrroloquinoline quinone drugs as a neuroprotectant and methods of use thereof

Abstract

The invention includes compositions comprising substantially purified pyrroloquinoline quinone, that are useful in methods for the treatment and prevention of acute and chronic neurological injury caused by peroxynitrite. The invention also includes methods for the treatment and prevention of neurological injury comprising contacting a composition of the invention with a human patient. In embodiments of the invention, pyrroloquinoline quinone is provided prior to formation of peroxynitrite.

What is claimed is:  
     
         1 . A method for preventing or inhibiting peroxynitrite-induced neurotoxicity in a mammalian subject in need thereof, comprising administering to said subject an effective amount of a pyrroloquinoline quinone compound, wherein peroxynitrite is not present in toxic levels in said mammalian subject, such that peroxynitrite-induced neurotoxicity is prevented or inhibited.  
     
     
         2 . The method of  claim 1 , wherein said pyrroloquinoline quinone is administered at a concentration between about 1 nM and less than about 100 μM.  
     
     
         3 . The method of  claim 1 , wherein said pyrroloquinoline quinone is administered at a concentration between about 1 μM and about 100 μM.  
     
     
         4 . The method of  claim 1 , wherein said pyrroloquinoline quinone is administered at a concentration between about 100 μM and about 500 μM.  
     
     
         5 . The method of  claim 1 , wherein said subject suffers from or is at risk of amyotrophic lateral sclerosis (ALS), and said method treats neurological manifestations of ALS.  
     
     
         6 . The method of  claim 1 , wherein said pyrroloquinoline quinone compound is formulated in polyethylene glycol or liposomes to enhance central nervous system absorption and efficacy.  
     
     
         7 . A method for preventing, inhibiting or reducing neurological damage incident to a stroke in a mammalian subject at risk thereof, comprising administering to said subject an effective amount of a pyrroloquinoline quinone compound prior to a measureable increase in peroxynitrite formation in said mammalian subject, such that neurological damage incident to stroke is prevented, inhibited or reduced.  
     
     
         8 . A method for preventing, inhibiting or reducing neurological damage incident to a ALS in a mammalian subject at risk thereof, comprising administering to said subject at risk of or suffering from ALS an effective amount of a pyrroloquinoline quinone compound prior to a measurable increase in peroxynitrite formation in said mammalian subject, such that neurological damage incident to ALS is prevented, inhibited or reduced.  
     
     
         9 . A method for treating a chronic neurological disorder in a mammalian subject in need thereof, comprising administering to said subject an effective amount of a pyrroloquinoline quinone compound at a point wherein peroxynitrite is not detectable at toxic levels, such that said chronic neurological disorder is reduced or eliminated.  
     
     
         10 . A method for inducing cell toxicity in tissue, comprising contacting said tissue with an effective amount of a pyrroloquinoline quinone compound, wherein said pyrroloquinoline quinone compound is capable of interacting with peroxynitrite, such that neural cell death increases.  
     
     
         11 . The method of  claim 10 , wherein said tissue is neural tissue.  
     
     
         12 . The method of  claim 11 , wherein said neural tissue comprises a malignant cell.  
     
     
         13 . A method for preventing or inhibiting peroxynitrite-induced cell death in a mammalian subject at risk of or undergoing an acute traumatic neurological event, comprising administering to said subject an effective amount of a pyrroloquinoline quinone compound at such time wherein peroxynitrite is not detectable at toxic levels, such that peroxynitrite-induced cell death is prevented or inhibited.  
     
     
         14 . A method for preventing or inhibiting peroxynitrite-induced neurotoxicity in a mammalian subject in need thereof, comprising administering to said subject an effective amount of a pyrroloquinoline quinone compound, whereby superoxide levels are reduced, such that peroxynitrite-induced neurotoxicity is prevented or inhibited.  
     
     
         15 . A method for reducing endogenous peroxynitrite levels in a mammalian subject in need thereof, or in a cell, tissue or organ of said mammalian subject, by administering to said subject or said cell, tissue or organ thereof an effective amount of a pyrroloquinoline quinone compound, such that the endogenous peroxynitrite levels are reduced or at least maintained.  
     
     
         16 . A kit for treating or preventing a neurotoxic injury, comprising in one or more containers pyrroloquinoline quinone, a pharmaceutically acceptable carrier, and instructions for use of said kit.  
     
     
         17 . A method of treating or preventing a neurotoxic injury, comprising administering to a subject at risk of an imminent neurotoxic injury caused by increased peroxynitrite levels, comprising administering, when peroxynitrite levels are not yet neurotoxic, a combination therapy including a PQQ compound and a second antioxidant, such that said neurotoxic injury is treated or at least partially alleviated.  
     
     
         18 . A method for preventing or inhibiting peroxynitrite-induced injury to white matter in a mammalian subject in need thereof, comprising administering to said subject an effective amount of a pyrroloquinoline quinone compound, wherein peroxynitrite is not present in toxic levels in said mammalian subject, such that peroxynitrite-induced injury to white matter is prevented or inhibited.  
     
     
         19 . The method of  claim 18 , wherein said white matter comprises one or more oligodendrocytes.  
     
     
         20 . The method of  claim 18 , wherein said mammalian subject is suffering from or at risk of cerebral palsy or multiple sclerosis.